EP2718263A1 - Method for preparing highly purified benidipine hydrochloride - Google Patents
Method for preparing highly purified benidipine hydrochlorideInfo
- Publication number
- EP2718263A1 EP2718263A1 EP11827762.3A EP11827762A EP2718263A1 EP 2718263 A1 EP2718263 A1 EP 2718263A1 EP 11827762 A EP11827762 A EP 11827762A EP 2718263 A1 EP2718263 A1 EP 2718263A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- benidipine hydrochloride
- ultrasound
- benidipine
- dissolved
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention belongs to medicine field and relates to a method of preparing highly purified benidipine hydrochloride by ultrasonic technology.
- the method of the present invention comprises: 1) during the pre-treatment stage, including acylchloridizing the main ring of dihydropyridine and then linking the side chain to synthesize directly benidipine hydrochloride, ultrasound technology is introduced, and the reactant material is dispersed and dissolved by ultrasound, and/or 2)during the post-treatment stage, ultrasonic technology is introduced and crude crystal (or product obtained by heating to dryness) of benidipine hydrochloride obtained via the method described above or other possible synthetic routes is dissolved once more and then highly purified benidipine hydrochloride is obtained by ultrasound.
- Benidipine hydrochloride whose chemical name is ( ⁇ )-(R*)- 1 ,4-dihydro-2,6-dimethyl-4-(meta-nitrophenyl)-3 ,5-pyridinedica rbolate methyl ester [(R*)-l-benzyl-3-piperidine alcohol ester], belongs to dihydropyridine receptor antagonist. It can bind to dihydropyridine receptors at the binding site with high affinity and high specificity, and shows a strong inhibitory effect on Ca channel. Benidipine not only has an inhibitory effect on muscular (L-type) Ca channel, but also has an inhibitory effect on voltage-dependent N- and T-type Ca channels.
- benidipine has highly affinity with cell membrane, has vascular selectivity and renal protection effect. Therefore, it is an ideal, safe and effective agent for the treatment of hypertension and renal parenchymal hypertension and angina.
- benidipine hydrochloride has 4 optical isomers: (S)-(S)-(+)-a, (R)-(R)-(-)-a, (R)-(S)-(+) ⁇ and (S)-(R)-(-) ⁇ , and the active ingredients for drug are the mixture of (S)-(S)-(+)-a and (R)-(R)-(-)-0L Therefore, it is necessary to separate a and ⁇ isomers during the post- treatment stage of benidipine hydrochloride preparation.
- the routes involve the synthesis of the main ring later includes the following; 1) synthesizing the main ring via ⁇ -aminocrotonate; 2) synthesizing the main ring via acetylacetate ester; 3) the One-pot' method involving 3-nitrobenzaldehyde, ⁇ -aminocrotonate and acetylaceate ester.
- JP2007-8819A thus disclosed a method for preparing highly purified benidipine hydrochloride meeting pharmaceutical use by first preparing the monohydrate of benidipine hydrochloride.
- the present invention mainly uses the direct synthesis method of benidipine hydrochloride including acylchloridizing main ring of dihydropyridine and then linking the side chain.
- Figure 1 is a liquid chromatography of benidipine hydrochloride crude crystal or product obtained by heating to dryness using HPLC area normalization method
- Figure 2 is a liquid chromatography of ultrasound crystal obtained using HPLC area normalization method
- Figure 3 is a liquid chromatography of mother liquor after crystallization by ultrasound using HPLC area normalization method.
- suitable temperature for ultrasound crystallization is -78 ° C ⁇ 100 ° C , preferably -5 ° C to 30 ° C .
- Suitable ultrasound frequency is 20 kHz— 500 kHz, preferably 20 kHz— 100 kHz.
- Suitable ultrasound power is 1 mW— 5000 W, preferably 1 W— 500 W.
- the duration of the ultrasound is 1 minute to 24 hours, preferably 3 minutes to 120 minutes.
- Suitable solvent for preparing benidipine hydrochloride under ultrasound is lower-carbon-number ketone, lower-carbon-number alcohol, lower-carbon-number ether, lower-carbon-number acid, lower-carbon-number ester, dichloromethane, chloroform, acetic anhydride or commonly used small molecule solvents.
- Preferred solvents are selected from the group consisting of acetone, ethanol, methanol, ⁇ , ⁇ -dimethylformamide (DMF), acetonitrile, diethyl ether, dichloromethane and water.
- dihydropyridine main ring [chemical name: 2,6-dimethyl-4-(3-nitrophenyl)-l,4- dihydropyridine-3,5- dicarboxylic acid monomethyl ester] is dispersed evenly in appropriate amount of mixed solution of ⁇ , ⁇ -dimethylformamide (DMF) and dichloromethane.
- DMF ⁇ , ⁇ -dimethylformamide
- dichloromethane ⁇ , ⁇ -dimethylformamide
- the resultant suspension is cooled in ice-bath condition, and thionyl chloride is added.
- reaction solution is washed with water and saturated saline for several times. Solvent is recycled to obtain crude crystal of benidipine hydrochloride (containing a and ⁇ isomers, and other related substances).
- Fig. 1 is a liquid chromatography of benidipine hydrochloride crude crystal or product obtained by heating to dryness using HPLC area normalization method;
- Fig. 2 is a liquid chromatography of ultrasound crystal obtained using HPLC area normalization method
- Fig. 3 is a liquid chromatography of mother liquor after crystallization by ultrasound using HPLC area normalization method.
- dihydropyridine main ring i.e.,[2,6-dimethyl -4-(3-nitrophenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester] was placed into 200 mL reaction flask, and 14 mL ⁇ , ⁇ -dimethylformamide (DMF) and 56 mL dichloromethane was added. To the resultant homogeneous suspension was added 2.4 mL of thionyl chloride under ice-bath, then the mixture was stirred for 1 hour to obtain a clear solution.
- DMF ⁇ , ⁇ -dimethylformamide
- pyridine (alcohol) side chain i.e., [l-benzyl-3 -hydroxypiperidine] was added and stirred for 2.5 hours under ice-bath.
- the reaction solution was washed with 40 mL water ( x 4) and 40 mL saturated saline solution (x 1).
- the dichloromethane solution was dried for two hours by adding 4 g of anhydrous sodium sulfate. Then, sodium sulfate solid was removed by filtering, and dichloromethane was recycled under reduced pressure to obtain a yellow to red crude crystal (herein after referred to as crude crystal of benidipine hydrochloride).
- the crude crystal mentioned above was dissolved in 100 mL acetone, and ultrasounded at 150 W and 40 MHz for 7 minutes, filtered under reduced pressure and dried to obtain 5.9 g of crystal as yellow powder (yield 36.2%).
- Mobile phase mixed solution of 0.05 mol/L potassium dihydrophosphate solution (pH 3.0): methanol : tetrahydrofuran (65:27:8)
- Flow rate adjusted to render the retention time of benidipine hydrochloride to be about 20 min.
- Chromatogram record time about 2 times of the peak time of benidipine hydrochloride
- Example 1 The purity of benidipine hydrochloride obtained in Example 1 was detached to be ⁇ 98.6%.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2011100968409A CN102746215A (en) | 2011-04-18 | 2011-04-18 | Method for preparing high-purity benidipine hydrochloride |
PCT/CN2011/080293 WO2012142815A1 (en) | 2011-04-18 | 2011-09-28 | Benidipine hydrochloride |
Publications (3)
Publication Number | Publication Date |
---|---|
EP2718263A1 true EP2718263A1 (en) | 2014-04-16 |
EP2718263A4 EP2718263A4 (en) | 2015-01-21 |
EP2718263B1 EP2718263B1 (en) | 2016-04-20 |
Family
ID=47026771
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP11827762.3A Not-in-force EP2718263B1 (en) | 2011-04-18 | 2011-09-28 | Method for preparing highly purified benidipine hydrochloride |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP2718263B1 (en) |
JP (1) | JP5878975B2 (en) |
KR (1) | KR101387129B1 (en) |
CN (1) | CN102746215A (en) |
WO (1) | WO2012142815A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2700632A4 (en) * | 2011-04-18 | 2014-09-03 | Hefei Beini Medical Technology Company Ltd | Method for purification of calcium channel blockers of dihydropyridine type and preparation of nanoparticles thereof |
CN103641774B (en) * | 2013-11-26 | 2015-07-08 | 湖南方盛制药股份有限公司 | Preparation method of benidipine hydrochloride |
KR102024896B1 (en) * | 2016-03-24 | 2019-09-24 | 주식회사 엘지화학 | Process for the preparation of bisphenol A |
US10695329B2 (en) | 2016-10-07 | 2020-06-30 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
EP3773574A4 (en) | 2018-04-11 | 2022-03-02 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
CN112679416A (en) * | 2020-12-31 | 2021-04-20 | 济南朗科医药技术有限公司 | Preparation method of benidipine hydrochloride |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS57171968A (en) * | 1981-04-17 | 1982-10-22 | Kyowa Hakko Kogyo Co Ltd | 1,4-dihydropyridine derivative |
JPS59137461A (en) * | 1983-01-27 | 1984-08-07 | Kyowa Hakko Kogyo Co Ltd | 1,4-dihydropyridine derivative |
JPS5970667A (en) * | 1982-10-15 | 1984-04-21 | Kyowa Hakko Kogyo Co Ltd | 1,4-dihydropyridine derivative |
AU557175B2 (en) * | 1982-10-15 | 1986-12-11 | Kyowa Hakko Kogyo Co. Ltd. | 2,6-dimethyl-4-(3-nitro phenyl)-1,4-dihydro pyridine-3,5- dicarboxylic acid esters |
JPS61158962A (en) * | 1985-01-07 | 1986-07-18 | Teijin Ltd | Production of 1,4-dihydropyridine derivative |
GB8615314D0 (en) * | 1986-06-23 | 1986-07-30 | Ici Plc | Chemical process |
JP3053861B2 (en) * | 1990-11-30 | 2000-06-19 | 協和醗酵工業株式会社 | 1,4-dihydropyridine derivative |
JP3238165B2 (en) * | 1991-07-10 | 2001-12-10 | 株式会社豊田中央研究所 | Herapite derivative |
FR2690441A1 (en) * | 1992-04-08 | 1993-10-29 | Rhone Poulenc Agrochimie | New triazole derivatives and imidazole fungicides. |
GB9624615D0 (en) * | 1996-11-26 | 1997-01-15 | Zeneca Ltd | Chrystallisation process |
DE10137017A1 (en) * | 2001-07-30 | 2003-02-20 | Basf Ag | Crystallization process for the adjustment of small particles |
GB0216700D0 (en) * | 2002-07-18 | 2002-08-28 | Astrazeneca Ab | Process |
US20050032873A1 (en) * | 2003-07-30 | 2005-02-10 | Wyeth | 3-Amino chroman and 2-amino tetralin derivatives |
JP4544895B2 (en) * | 2004-03-31 | 2010-09-15 | 大日本印刷株式会社 | Method for producing dihydropyridine derivatives |
JP3763538B1 (en) * | 2005-06-28 | 2006-04-05 | ダイト株式会社 | Industrial production method of high-purity benidipine hydrochloride |
JP2010083925A (en) * | 2008-09-29 | 2010-04-15 | Fujifilm Corp | Dispersion of slightly soluble compound and method for manufacturing the same, recording liquid using the same, ink set, printed matter, image formation method, and image forming device |
JP5590228B2 (en) * | 2011-04-18 | 2014-09-17 | ヘフェイ ベイニ メディカル テクノロジー カンパニー リミテッド | Preparation method of nanoparticles of Benidipine hydrochloride |
EP2700632A4 (en) * | 2011-04-18 | 2014-09-03 | Hefei Beini Medical Technology Company Ltd | Method for purification of calcium channel blockers of dihydropyridine type and preparation of nanoparticles thereof |
-
2011
- 2011-04-18 CN CN2011100968409A patent/CN102746215A/en active Pending
- 2011-09-28 JP JP2014505487A patent/JP5878975B2/en active Active
- 2011-09-28 WO PCT/CN2011/080293 patent/WO2012142815A1/en active Application Filing
- 2011-09-28 KR KR1020127013098A patent/KR101387129B1/en not_active IP Right Cessation
- 2011-09-28 EP EP11827762.3A patent/EP2718263B1/en not_active Not-in-force
Non-Patent Citations (2)
Title |
---|
No further relevant documents disclosed * |
See also references of WO2012142815A1 * |
Also Published As
Publication number | Publication date |
---|---|
CN102746215A (en) | 2012-10-24 |
EP2718263B1 (en) | 2016-04-20 |
WO2012142815A1 (en) | 2012-10-26 |
KR101387129B1 (en) | 2014-04-21 |
WO2012142815A8 (en) | 2013-01-03 |
EP2718263A4 (en) | 2015-01-21 |
JP2014511881A (en) | 2014-05-19 |
JP5878975B2 (en) | 2016-03-08 |
KR20130025859A (en) | 2013-03-12 |
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